Project Summary: The high heritability of schizophrenia indicates that identification of risk genes will provide fundamental information regarding the pathophysiological mechanisms of schizophrenia. Despite numerous patient studies, however, only a few schizophrenia risk genes have been strongly implicated and, importantly, their functional relevance to pathophysiology remains unknown. Investigation of biological markers of schizophrenia progression and the role of genetic variation would provide important information to the underlying biology of this disorder. The objective of the Genetics Core is to provide state-of-the-art genetic techniques and analyses to support the four CIDAR projects to investigate the role of genetic variation in putative markers of progression in schizophrenia. This application proposes to test genes with prior evidence for involvement in schizophrenia and with strong biological hypotheses for a role in one or more progression markers. The progression markers that will be investigated for genetic association include changes in event-related potentials and gray matter, white matter connections, cognitive measures, structural and functional brain region measures, and hormone levels. The central hypothesis is that genetic variation leads to variation in these indices of schizophrenia progression. This hypothesis will be tested by pursuing the following specific aim: 1) Identify genetic variation in candidate genes that contributes to progression of schizophrenia. It is postulated that progression of schizophrenia is controlled by genes. Furthermore, our working hypothesis is that genetic associations will be detected between the progression biomarkers examined by the CIDAR projects (Cognitive Function, Hormones and Sex Effects, ERPs and Gray Matter, and White Matter) and single nucleotide polymorphisms (SNPs) and haplotypes of specific candidate genes. The proposed research is significant to advance understanding of schizophrenia because it will provide crucial data on the role of genetic variation in progression of this disease. Relevance to Public Health: Schizophrenia is an important genetic disorder that will be better understood once the susceptibility genes are identified and their impact on pathophysiology is understood. The proposed research will have an important positive impact because it is expected to identify genes that contribute to schizophrenia progression that will provide new opportunities for identification of the molecular causes of schizophrenia and the development of therapeutic interventions that will aid patients and their families.